The IL-33/ST2 axis plays a protective role in T cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33^-/- mice displayed more severe Con A liver injury than WT mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33^-/- mice was associated with significantly higher levels of TNF-α and IL-1-β and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL10) and IL-17 was not significantly varied between WT and IL-33^-/- mice following Con A-hepatitis. The percentage of CD25⁺ NK cells was significantly higher in the livers of IL-33^-/- mice than in WT mice in association with up-regulated expression of CXCR3 in liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33^-/- mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4⁺ and CD8⁺ T cells, and the frequency of ST2⁺ Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2⁺Treg cells and control of NK cells.